8-SUBSTITUTED 10-PIPERAZINE-10,11-DIHYDRODIBENZO(b,f) THIEPINES

ABSTRACT

8-substituted 10-piperazino-10,11-dihydrodibenzo (b,f) thiepines having the formula   WHEREIN R1 is alkyl, alkoxy, alkylthio having one to four carbon atoms, or trifluoromethyl, R2 is hydrogen or hydroxyalkyl having two to four carbon atoms, and the pharmaceutically acceptable salts thereof having valuable pharmacodynamic activity and being suitable for use as neuro- and psychotropic medicaments.

United States Patent [191 Protiva et al.

' 1 Apr. 3, 1973 154] S-SUBSTITUTED IO-PIPERAZINE- 10,1l-DIHYDRODIBENZO(B,F) THIEPINES [75] Inventors: Miroslav Protiva; KarelPelz; Jirina Metysova, all of Praha, Czechoslovakia [73] Assignee:Spofa, United Pharmaceutical [30] Foreign Application Priority Data Mar.24, 1969 Czechoslovakia ..2095/69 [52] U.S. Cl. ..260/268 TR, 260/327 B,424/250 [51] Int. Cl. ..C07d 51/70 [58] Field of Search ..260/268 TC,327 B [56] References Cited UNITED STATES PATENTS 3,563,993 2/1971Schindler et a1 ..260/268 TR 3,351,599 1 1/1967 Protiva ..260/268 TR3,359,271 12/1967 Schindler ..260/268 TR 3,379,729 4/1968 Protiva..260/268 TR 3,509,154 4/1968 Fouche ..260/268 TR 3,337,554 8/1967 Jilek..260/268 TR 3,462,436 8/1969 Fouche ..260/268 TR OTHER PlJBLlCATlONSJilek et al. 111 Cocc. Czech. Chem. Common Vol. 36, p. 2226-2227 (June1971) Primary Examiner-Donald G. Daus Attorney-Michael S. Striker I [57]ABSTRACT v 8-substituted IO-piperazino- 1 0,1 l-dihyd rodibenzo (bf)thiepines having the formula valuable pharmacodynamic activity and beingsuitable for use as neuroand psychotropic medicaments.

3 Claims, No Drawings S-SUBSTITUTED IO-PIPERAZINE-IQJ l- DIHYDRODIBENZO(B,F)

This'invention relates to a novel series of 8.-substitutedl-piperazino-10,ll-dihydrodibenzo (bJ) thiepines having valuabletherapeutic properties.

The 8-substituted -piperazino-l0,l ldihydrodibenzo (bj) thiepines of theinvention are characterized by the following formula:

Included within the scope of the invention are the salts of the basesshown by formula I.

The bases and their salts demonstrate phars macodynamic activity and areparticularly suitable for use as neuroand psychotropic agents.

The compounds of the invention are also characterized by a very markedcentral inhibiting activity, high cataleptic activity, antiserotonin-,antihistamine and vasodilating'activity.

A typical compound in accordance with the invert.- tions, i.e.8-rnethylthio-. 1 Q-[ 4.-.( 3-hydroxypropyl )piperazino1- 1 0,1l-dihydrodibenzo thiepine in the form of its dihydrochloride-dihydratewas evaluated for its pharmalogical. activity.

Its acute toxicity was determined in the mouse after intravenousinjection. The LDSO thus, determined amounted to 44 mg/kg. In the testwith the rotating bar, following intravenous administration in themouse, there were observed already with small dosages, disturbances ofcoordination of movements; the average dose in this test (EDSO) in theperiod of maximal activity minutes, following administration of the testcompound) amounted to 0.11 mg/kg; the test compound further acts topotentiate the thiopental narcosis in the mouse following intravenousadministration. The threshhold dose, which, statistically significantly,prolongs the thiopental sleep amounts to 0.025 mg/kg. In thecatalepsytest carried out in rats, the compound demonstrated highactivity; the dose which relieves cataleptic symptoms in 50 percent ofthe animals following intraperitoneal administration (EDSO) amounts to0.62 mg/kg. In doses of 0.1 rng/kg the instant compound, followingintroperitoneal administration, produces an antiseritonin activity intherat in, invivo testing. When doses of 10 mg/kgi.p. were used in themouse, there was no effect on the reserpine response; following oraladministration of 50 mg/kg there is barely i.e., a statisticallyinsignificant effect on the ulcerogenic activity of reserpine in therat. Finally the compound evidenced a marked antihistamine ac.- tivityin the guinea pig in vivo in the histamine-detoxification test, as wellas a marked hypothermic activity, vessel dilating and an inflammationinhibiting effect.

In comparison tests with the known neuroleptic agent chlorpromazine thecompound of the invention was five times more effective thanchlorprornazzine i the following compounds: 8-methoxy-l0-piperazino-.

in the rotating bar test, 10 timesmore effective in the test forthiopentalnarcosis potentiation, about 13 times more effective in thecatalepsy test and slightly less toxic than the known compound. Itsworking or therapeutic index is thus much more favorable than that ofchlorpromazine.

The compounds of the invention are prepared by reacting an ester of thealcohol having the following formula wherein R has the same significanceas given. in Formulal and advantageously the corresponding halogenide,alkaneor arensulfonate, with a pipera zine having the formula lIN NR10,1 l-dihydrodibenzo (bfi thiepine; 8-methylthio-10- piperazino- 10,11-dihydrodibenzo (bj) thiepine; 8- rnethoxyl0- [4-( 3-hydroxypropyl-piperazino 10, 1 l dihydrodibenzo (bj) thiepine; 8-methylthio-10-[4-(3-hydroxypropyl)piperazino]- 1 0, l l-dihydrodibenzo i) h p n t 10, l 1-dihydrodibenzo As starting materials. for use in the process of theinvention, i.e.,as the component having formula 11, there may bementioned 8.-methoxy-10-chloro.-l0,l 1- dihydrodibenzo (bj) thiepine;8-methylthio- 10-chloro- (bf) thiepine; and 8- I trifluoromethyllO-chloro- 10 1. 1 -dihydrodibenzo (b J) thiepine whose preparation hasbeen described by K. Pelz et al., Collection Czechoslov. Chem. Commun.33, 1895,, 1968. As reaction component having formula III i.e., thepiperazine component, there may be I advantageously usedl-(2-hydroxyethyl)piperazine; 1-( 3,- hydroxypropyl) piperazine;1,-(4-hydroxybutyl) piperazine; and 1- (3-hydroxybutyl) piperazine.

The substitutionv reaction can be carried out with or without a solvent,that is,.with the excess of piperazine A component serving as reactionmedium. When a sol- The following examples are, given for furtherillustrating the invention, but are in no wise to be construed aslimiting the same.

EXAMPLE 1 A solution of 15.0 g 8-methoxy-lO-chloro-l0,l1- dihydrodibenzo(bf) thiepine and 22.0 g anhydrous piperazine in 30 ml chloroform wereheated together for 6 hours under reflux in a boiling water bath.Thereafter the chloroform was evaporated off under reduced pressure andthe residue distributed by shaking between 150 ml benzene and 150 mlwater. The benzene layer was separated off, washed with 100 ml water andshaken with 100 ml 3NHC1. There, then separated out the solidhydrochloride of the reaction product. After 1 hour of standing, thesolid material was separated off with suction, the acid aqueous phase(separated from the filtrate) added and the resultant mixture madealkaline with aqueous ammonia. The separated base was then extractedwith benzene, the extract dried with anhydrous potassium carbonate andevaporated. There were thusly recovered 12.1 g 8-methoxy-l-piperazine-l0,l l-dihydrodibenzo (bf) thiepine as a crudebase. The base was neutralized in an ethanolic solution with 2equivalents of maleic acid. Following the addition of ether, thereseparated out of the ethanolic solution the crystallinedi(hydrogenmaleate) of the base 8-methoxylO-piperazine-l0,lldihydrodibenzo (bf) thiepine which melted at 155-157C (ethanol-ether).

EXAMPLE 2 The procedure of Example 1 was followed and by reaction of16.0 g 8-methylthio-10-chloro-10,11- dihydrodibenzo (bf) thiepine with22.0 g anhydrous piperazine in ml chloroform, there were obtainedEXAMPLE 3 A mixture of 8.0 g 8-methoxy-10-chloro-l0,l ldihydrodibenzo(bf) thiepine and 5.5 g l-(3-hydroxypropyl) piperazine was heated for 3hours in a water bath at a temperature of 120-125 C. Following cooling,the reaction mixture was diluted with ml water and extracted withbenzene. The benzene solution was washed with water and then extractedwith 100 ml 3N HCl. The separated hydrochloride was suctioned off, addedto the aqueous phase (separated from the filtrate) and made alkalinewith an excess of 15 percent sodium hydroxide solution. The freed basewas extracted with benzene, the extract dried with anhydrouspotassiumcarbonate and evaporated. The crude base8-methoxy-10-[4-(3-hydroxypropyl)-piperazino1-0, ll-dihydrodibenzo (b,f) thiepine was recovered in a yield of 7.8 g. Following neutralizationwith maleic acid, the base was crystallized out as thedi(hydrogenmaleate) melting at l l41 15 C (ethanol).

EXAMPLE 4 Using a procedure analogous to that of Example 3, 8.0 g8-methylthio-lO-chloro-lO,ll-dihydrodibenzo (bf) thiepine were reactedwith 11.8 g l-(3-hydroxypropyl) piperazine at a temperature of C for areaction period of 6 hours. The isolation procedure described in theforegoing Example was followed and there were recovered 9.9 g of thecrystalline base of 8- methylthio-l0-[4-(3-hydroxypropyl)-piperazino]10,11-dihydrodibenzo (bf) thiepine having a melting point of 9395 C(benzene-petroleum ether). Following neutralization with HCl inethanolic solution the corresponding crystalline dihydrochloride, as thedihydrate separated out. The compound had a melting point of 223226 C(water-ethanol-ether).

What is claimed as new and desired to be protected by Letters Patent isset forth in the appended 1. A compound selected from the groupconsisting of S-methoxy- 1 0-4-( 3-hydroxypropyl)piperazino] 10,1l--dihydrodibenzo(bf) thiepine and 8-methylthio-10-[4-(hydroxypropyl)piperazino]- 1 0,1 ldihydrodibenzo(bf)thiepine.

2. The compound according to claim 1 designated 8- methoxy-l0-[4-(3-hydroxypropyl)piperazino]-10,1 ldihydrodibenzo(bf)thiepine.

3. The' compound according to, claim 1 designated 8-methylthiol0[4-(3-hydroxypropyl)piperazino]- l 0,1 1-dihydrodibenzo(bf)thiepine.

2. The compound according to claim 1 Designated8-methoxy-10-(4-(3-hydroxypropyl)piperazino)-10,11-dihydrodibenzo(b,f)thiepine.
 3. The compound according to claim 1designated8-methylthio-10(4-(3-hydroxypropyl)piperazino)-10,11-dihydrodibenzo(b,f)thiepine.